1. Field of the Invention
The present invention relates to a potassium channel opener.
2. Background Art
Calcium-activated potassium channel (alternatively referred to as “BK channel”) is present on cell membranes and is a protein which makes potassium ions permeate selectively. This channel protein has a calcium binding domain in an amino acid sequence facing intracellularly, and has a property of enhancing channel activity by binding of calcium. This means, the increase of intracellular calcium concentration leads to a higher chance of opening of the calcium-activated potassium channel (opening probability), thereby leading to an increase in permeability of cell membrane for potassium. There have been known three kinds of calcium-activated potassium channels, among which large conductance calcium-activated potassium channels are present in smooth muscles which are constituents of various kinds of organs, including blood vessel, bladder, bronchial tube, gastrointestinal tract, etc., and central or peripheral neuronal cells, however, they are not expressed in cardiac muscles.
Membrane potential is dependent on a balance of permeabilities of cell membrane for ions such as sodium, potassium, chloride, calcium, etc. When the potassium channel opening is selectively increased, potassium permeability becomes dominant, and cell is hyperpolarized. Therefore, opening of the calcium-activated potassium channels, for example, hyperpolarizes smooth muscle cells, lowers activities of voltage-dependent calcium channels, and inhibits influx of calcium from extracellular fluid. As a result, intracellular concentration of calcium decreases, leading to a relaxation of a smooth muscle. Accordingly, the opening of the calcium-activated potassium channels will make smooth muscle tissues relaxed, which are constantly under contraction (hypertension) in pathological states such as essential hypertension, tonic bladder, airway hyperresponsiveness, etc.
It also exhibits an inhibitory effect on hyperactivity, through hyperpolarization, in neuronal cells whose calcium concentration is increased due to hyperaction (hyperexcitement) caused by a strong stimulus. On the contrary, an administration of a BK channel blocker into central nervous system leads to convulsion in mice. As stated above, since pathological states due to a change in activity of potassium channels including calcium-activated potassium channels have recently become apparent, potential of treatment by potassium channel openers has been increased. Among them, a calcium-activated potassium channel opener is one of those that have been drawing most attention (Shieh, C. C., et al., Pharmacol. Rev., 52, pp. 557-593, 2000).
As a substance having effect of activating calcium-activated potassium channels, there have been known maxikdiol (Singh, S., et al., J. Chem. Soc. Perkin. Trans. I, pp. 3349-3352, 1994), dehydrosoyasaponin-I (MacManus, O. B., et al., Biocheminstry, 32, pp. 6128-6133, 1993) and L-735,334 (Lee, S. H., et al., J. Nat. Prod., 58, pp. 1822-1828, 1995), which are isolated from natural products, and as synthetic compounds, NS-1619 and its related compounds developed by NeuroSearch of Denmark, and Bristol-Myers Squibb of the United States (Olsen, S. P., et al., European patent publication No. 0477819A2, Olsen, S. P., et al., Euro. J. Pharmacol., 251, pp. 53-59, 1994), and the like.
However, dehydrosoyasaponin-I and L-735,334 have relatively high molecular weights, and drawbacks in terms of their functional mechanism. NS-1619 related compounds have low activities, and have a problem that their actions are not specific. Further, although maxikdiol has an excellent activity, it is extremely difficult to obtain, since it is a natural product. Therefore, there have been needs for development of an agent having a BK channel opening activity equivalent to or higher than that of maxikdiol, and having a high specificity of the activity.